20 痛觉
根据国际疼痛研究协会的说法,疼痛是一种与实际或潜在的组织损伤相关的不愉快的感觉和情绪体验,
者用这种损伤来描述。刺痛、灼痛、疼痛和酸痛是所有感觉形态中最独特的。与其他体感方式(触觉、压力和位
置感)一样,疼痛具有重要的保护功能,提醒我们注意需要逃避或治疗的伤害。在出生时对疼痛不敏感的儿
中,严重的伤害往往被忽视,并可能导致永久性组织损伤。然而,疼痛与其他体感方式或视觉、听觉和嗅觉不同,
因为它具有紧迫和原始的性质,具有强大的情感成分。
对疼痛的感知是主观的,受许多因素的影响。相同的感官刺激可以在不同条件下引起同一个人的截然不
的反应。例如,许多受伤的士兵在离开战场之前不会感到疼痛;受伤的运动员通常直到比赛结束才意识到疼痛。
简而言之,没有纯粹的“痛苦”刺激,即总是会引起所有人对疼痛感知的感官刺激。疼痛感知的可变性是我们在
前面几章中遇到的原则的另一个例子:疼痛不是感觉事件的直接表达,而是大脑中各种神经信号精心处理的
物。
当经历疼痛时,它可能是急性的、持续的,或者在极端情况下是慢性的。持续性疼痛是许多临床病症的
征,通常是患者就医的原因。相比之下,慢性疼痛似乎没有任何用处;只会让患者痛苦不堪。疼痛的高度个体化
和主观性是导致其难以客观定义和临床治疗的因素之一。
在本章中,我们将讨论构成正常人疼痛感知基础的神经过程,并解释临床上遇到的一些异常疼痛状态的
源。
20.1 有害损伤激活温度、机械和多模态伤害受体
周围的许多器官,包括皮肤和皮下结构,如关节和肌肉,都具有专门的感觉受体,这些受体会被伤害性损害
激活。与专门的轻触和压力体感受体不同,这些伤害受体中的大多数只是初级感觉神经元的游离神经末梢。
害受体主要分为 3 类:温度性伤害受体机械性伤害受体多觉性伤害性受体还有更神秘的第四类,称为寂静
性伤害性受体
温度性伤害受被极端温度激活,通常高于 45°C 或低于 5°C。如图 20.1.1A 所示,它们包括小直径的外围
末端,以 5 米每秒至 30 米每秒的速度传导动作电位的薄髓 Aδ 轴突和以小 1.0 米每秒的速度传导的无髓鞘
C 纤维轴突。施加在皮肤上的强烈压力可以最佳地激活机械伤害受体;它们也是有髓鞘的 Aδ 轴突的末端。多模
态伤害受体可以被高强度的机械、化学或热(热和冷)刺激激活。如图 20.1.1A 所示,此类伤害受体主要由无髓
C 纤维组成。
3 类伤害受体广泛分布于皮肤和深层组织中,并且经常被共同激活。如图 20.1.1B 所示,当锤子敲击您的
拇指时,您最初会感到剧烈疼痛(“第一次疼痛”,然后是更长时间的疼痛,有时甚至是灼痛(“第二次疼痛”
快速锐痛是由 Aδ 纤维传输的,该纤维携带来自受损的热和机械伤害受体的信息。缓慢的钝痛是由 C 传递
的,C 纤维传递来自多模态伤害受体的信号。
在内脏中发现了寂静性伤害性受体这类受体通常不会被伤害性刺激激活;相反,炎症和各种化学试剂
显著降低它们的放电阈值。它们的激活被认为有助于继发性痛觉过敏和中枢敏化的出现,这是慢性疼痛的 2
显著特征。
有害刺激使传入轴突的裸露神经末梢去极化并产生向中央传播的动作电位。这是如何实现的?伤害受体
膜包含将伤害性刺激的热能、机械能或化学能转化为去极化电位的受体。其中一种蛋白质是所谓的瞬时受体
离子通道大家族的成员。这种受体通道时受体电位香草醛受体 1 由伤害性神经元选择性表达,并介导辣椒
素、辣椒和许多其他刺激性化学物质的活性成分的疼痛产生作用。时受体电位香草醛受 1 通道也会被有害
热刺激激活,激活阈值约为 45°C,该温度会引发热痛。重要的是,瞬时受体电位香草醛受体 1 介导的膜电流因
酸碱值降低而增强,酸碱值是炎症化学环境的一个特征。
瞬时受体电位道家族的其他受体通道由伤害受体表达,是对从寒冷到高温的广泛温度感知的基础。特
感兴趣的是瞬时受体电位 M 8它是一种薄荷醇反应和冷敏感通道,可能介导许多化疗药物(如奥沙利铂)
20.1 有害损伤激活温度、机械和多模态伤害受体
Chapter 20 / Pain 471
In this chapter, we discuss the neural processes
that underlie the perception of pain in normal individ-
uals and explain the origins of some of the abnormal
pain states that are encountered clinically.
Noxious Insults Activate Thermal, Mechanical,
and Polymodal Nociceptors
Many organs in the periphery, including skin and sub-
cutaneous structures such as joints and muscles, pos-
sess specialized sensory receptors that are activated by
noxious insults. Unlike the specialized somatosensory
receptors for light touch and pressure, most of these
nociceptors are simply the free nerve endings of pri-
mary sensory neurons. There are three main classes of
B 第一次和第二次疼痛
A 复合动作电位
0
1
2
3
4
5
6
0102030405060708090
时间(毫秒)
波幅(毫伏)
Aα, Aβ
Aδ
C
Aα, Aβ
Aδ
0 0.4 0.8 1.21.6 2.0 2.4 2.8
时间(毫秒)
第一次疼痛 第二次疼痛
疼痛强度
时间
薄髓鞘
Aδ 纤维
无髓的
C 纤维
nociceptors—thermal, mechanical, and polymodal—
as well as a more enigmatic fourth class, termed silent
nociceptors.
Thermal nociceptors are activated by extremes in tem-
perature, typically greater than 45°C (115°F) or less than
5°C (41°F). They include the peripheral endings of small-
diameter, thinly myelinated Aδ axons that conduct action
potentials at speeds of 5 to 30 m/s and unmyelinated
C-fiber axons that conduct at speeds less than 1.0 m/s
(Figure 20–1A). Mechanical nociceptors are activated opti-
mally by intense pressure applied to the skin; they too
are the endings of thinly myelinated Aδ axons. Polymodal
nociceptors can be activated by high-intensity mechani-
cal, chemical, or thermal (both hot and cold) stimuli. This
class of nociceptors consists predominantly of unmyeli-
nated C fibers (Figure 20–1A).
Kandel-Ch20_0470-0495.indd 471 18/01/21 5:54 PM
20.1.1: 不同类别的伤害感受纤维中动作电位的传播。A. 传导动作电位的速度是每根纤维横截面直径的函数。
图中的波峰按等待时间的字母顺序标记。第一个峰值及其细分是有髓 A 纤维的电活动总和。延迟(缓慢传导)
转代表无髓鞘 C 纤维的总动作电位。A 纤维的复合动作电位显示在更快的时基上,以描述几种纤维动作电位的
总和
[165]
B. 第一次和第二次疼痛分别由 Aδ C 纤维传递
[166]
408
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
生的极度冷超敏反应。如图 20.1.2 所示,瞬时受体电位锚定蛋白 1 对各种刺激物有反应,从芥末油到大蒜,甚至
是空气污染物。最近,描述了一个机械换能器系列(Piezo1 Piezo2(第 18 章)。这些通道可能是机械超敏反
应的重要贡献者,机械超敏反应是许多慢性疼痛病症的一个突出特征。
除了这个瞬时受体电位道群之外,感觉神经元还表达参与外周刺激转导的许多其他受体和离子通道。
害受体选择性地表达许多不同的电压门 Na
+
通道,这些通道是局部麻醉剂的目标,可以有效地阻止疼痛(想
想可以完全消除牙痛的牙医)伤害受体表达对河豚毒素敏感或有抵抗力的 Na
+
通道。一种类型的河豚毒素敏感
通道 Nav1.7 是人类感知疼痛的关键分子机制,正如在相应 SCN9A 因中具有功能丧失突变的罕见个体中所揭
示的那样。这些人对疼痛不敏感,但在其他方面都很健康,对触觉、温度、本体感觉、挠痒痒和压力表现出正常
的感觉反应。SCN9A 基因中的第二类突变导致伤害受体过度兴奋;具有这些突变的个体表现出一种称为红斑性
肢痛症的遗传病症,其中四肢有剧烈、持续的灼痛,并伴有极度发红(血管扩张)由于 Nav1.7 与许多其他电压
门控 Na
+
通道不同,它不存在于中枢神经系统中,因此制药公司正在开发拮抗剂,有望提供一种调节疼痛过程
的新方法,而不会出现全身给药可能产生的不良副作用利多卡因,可阻断电压门控 Na
+
通道的所有亚型。
伤害受体还表达一种离子型嘌呤能受体 PTX3该受体在组织损伤后由外周细胞释放的三磷酸腺苷激活。
外,如图 20.1.3 所示,它们还表达 Mas 相关三磷酸鸟苷结合蛋白偶联受体家族的成员,该家族可被肽配体激
并用于使伤害受体对其局部环境中释放的其他化学物质敏感。这些无髓鞘传入神经的子集还包括对各种引起
痒的物质(包括致痒剂组胺和氯喹)有反应的受体通道。因此,这些受体和通道是开发选择性药物的有吸引
的目标,这些药物对感觉神经元有反应,对疼痛和瘙痒刺激有反应。
不受控制的伤害受体激活与多种病理状况有关。伤害受体活动改变导致的 2 种常见疼痛状态是异常性疼痛
和痛觉过敏。异常性疼痛患者对通常无害的刺激会感到疼痛:轻微抚摸晒伤的皮肤、类风湿性关节炎患者的
节运动,甚至是剧烈运动后早上起床的行为。然而,异常性疼痛患者不会持续感到疼痛;在没有外周刺激的情况
下,就没有疼痛。相比之下,痛觉过敏患者(对伤害性刺激的过度反应)通常会在没有感觉刺激的情况下报告持
续性疼痛。
持续性疼痛可分为两大类,伤害性疼痛和神经性疼痛。伤害性疼痛由皮肤或软组织中伤害受体的激活引起,
以响应组织损伤,并且通常伴随炎症发生。扭伤和拉伤会产生轻微形式的伤害性疼痛,而关节炎或侵入软组
的肿瘤会产生更严重的伤害性疼痛。通常,伤害性疼痛用甾体类抗炎药治疗,或者在严重时用吗啡等阿片
药物治疗。
神经性疼痛由外周或中枢神经系统的神经直接损伤引起,通常伴有烧灼感或电击感。神经性疼痛包括复
的局部疼痛综合症,即使是对肢体周围神经的非常轻微的损伤也会导致这种疼痛;带状疱疹后遗神经痛,许多患
者在带状疱疹发作后经历的剧烈疼痛;或三叉神经痛,一种由三叉神经未知病理引起的面部剧烈、剧烈的疼痛。
如图 20.1.4 所示,其他神经性疼痛包括肢体截肢后可能发生的幻肢痛。在某些情况下,甚至可以在没有外周刺
激的情况下发生自发的、持续的、通常是灼痛的疼痛,这种现象称为疼痛麻醉。在尝试通过消融三叉神经感觉神
经元来治疗三叉神经痛后,可能会触发该综合症。神经性疼痛对非甾体抗炎药没有反应,通常对阿片类药物
应不佳。最后,中枢神经系统的损伤,例如多发性硬化、中风后或脊髓损伤后,也可导致中枢神经性疼痛状态。
由于抑制性控制的丧失(如发生在癫痫中)是导致神经性疼痛的一个重要因素,因此毫不奇怪,神经性疼痛的一
线治疗涉及抗惊厥药,尤其是加巴喷丁类药物。(提及 γ-氨基丁酸是基于加巴喷丁与 γ-氨基丁酸的结构相似性。
然而,加巴喷丁实际上通过与电压门控 Ca
2+
通道的 α
2
δ-亚基结合发挥作用,最终减少神经递质释放)
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
伤害性刺激的感觉来自伤害性感觉神经元的外周轴突分支中的信号,其细胞体位于背根神经节。这些神
元的中央分支以高度有序的方式终止于脊髓。大多数终止于背角。如图 20.2.1B 所示,传递不同感觉方式的初级
传入神经元终止于不同的薄层,因此背角神经元的解剖组织、它们的接受特性和它们在感觉处理中的功能之
存在紧密联系。
背角最表层的许多神经元,称为 I 层或边缘层, Aδ C 纤维传递的有害刺激有反应。因为它们选择性地
对伤害性刺激做出反应,所以它们被称为伤害感受特异性神经元。这组神经元投射到中脑和丘脑。第二类 I 层神
409
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
Chapter 20 / Pain 473
细胞外侧
细胞质侧
瞬时受体电位
香草醛受体 4
瞬时受体电位
锚蛋白1
瞬时受体电位
香草醛受体 3
瞬时受体电位
香草醛受体 1
瞬时受体电位
M8
瞬时受体电位
香草醛受体 2
N
N
NN
N
N
CCCCCC
30°
10° 20°
40° 50°
60°
瞬时受体
电位M8
瞬时受体
电位香草
醛受体 4
瞬时受体电位
香草醛受体1
瞬时受体电位香草醛受体2
B 背根神经节细胞瞬时受体电位通道的热敏性
C 瞬时受体电位通道打开的通路
蛋白
激酶C
缓激肽
缓激肽受体
瞬时受体电位
香草醛受体1
三磷酸鸟苷
结合蛋白
三磷酸
鸟苷
内质网
磷酸
肌醇1,4,5-三磷酸
Ca
2+
Ca
2+
P
P
P
Ca
2+
磷脂
C
核糖核酸
28° 36° 44° 51°
A 非洲爪蟾卵母细胞瞬时受体电位通道的热敏性
Figure 20–2 Transient receptor potential ion channels in
nociceptive neurons.
A.Recordings from Xenopus oocytes injected with mRNA encod-
ing transient receptor potential (TRP) channels reveal the thermo-
sensitivity of the channels. The temperature (centigrade) at which
a specific TRP channel is activated is shown by the downward
deflection of the recording. (Photograph on left reproduced, with
permission, from Erwin Siegel 1987; traces on the right repro-
duced, with permission, from Tominaga and Caterina 2004.)
B.Temperature response profiles of different TRP channels
expressed by dorsal root ganglion neurons. (Adapted, with
permission, from Jordt, McKemy, and Julius 2003; Dhaka,
Viswanath, and Patapoutian 2006.)
C.Bradykinin (BK) binds to G protein–coupled receptors on
the surface of primary afferent neurons to activate phos-
pholipase C (PLC), leading to the hydrolysis of membrane
phosphatidylinositol bisphosphate (PIP
2
), the production of
inositol 1,4,5-trisphosphate (IP
3
), and the release of Ca
2+
from intracellular stores. Activation of protein kinase C (PKC)
regulates TRP channel activity. The TRPV1 channel is sensi-
tized, leading to channel opening and Ca
2+
influx. (Source:
Bautista et al. 2006.)
Kandel-Ch20_0470-0495.indd 473 18/01/21 5:54 PM
受体温度范围(摄氏度)
瞬时受体电位
锚蛋白1
磷脂酰肌
醇-4,5-二
20.1.2: 伤害性神经元中的瞬时受体电位离子通道。A. 注射了信使核糖核酸编码瞬时受体电位通道的非洲爪蟾
卵母细胞的记录揭示了通道的热敏感性。特定时受体电通道被激活的温度(摄氏度)由记录的向下偏转
[167]
B. 背根神经节神经元表达的不同时受体电位道的温度响应曲线
[139]
C. 缓激
1
与初级传入神经元
表面的三磷酸鸟苷结合蛋偶联受体结合以激活磷脂酶 磷脂酶 C,导致膜磷脂酰肌醇-4,5-二磷酸的水解,肌醇
1,4,5-三磷酸的产生,以及细胞内储存的 Ca
2+
的释放。蛋白激酶 C 的激活调节瞬时受体电位通道活性。瞬时受体
电位香草醛受体 1 通道被敏化,导致通道打开和 Ca
2+
流入
[168]
410
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
A
B
D
C
1 厘米
AB
14
12
10
8
6
4
2
机械性痛觉过敏
Flare
机械性疼痛阈值
烧伤前
烧伤后
A B C
20.1.3
: 痛觉过敏是由伤害受体的敏化引起的
[169]
A.
A
点和
D
点烧伤前后,记录了
A
B
C
点的机械疼
痛阈值。一名受试者的手上显示了由烧伤引起的发红(耀斑)和机械性痛觉过敏区域。在所有受试者中,机
痛觉过敏的面积大于耀斑面积。即使在耀斑消失后,机械性痛觉过敏仍然存在。B. 烧伤前后的平均机械痛阈值。
烧伤后疼痛的机械阈值显著降低。
正常 幻肢
正常 幻肢
B
在翻唇任务中大脑皮层活跃的区域
脊髓
手臂
A 上行脊髓输入的皮层表征
20.1.4: 幻肢痛中神经激活的变化。A. 在幻肢痛患者中,由上行脊髓感觉输入激活的大脑皮层区域扩大。B.
肢痛患者和健康对照者在噘嘴任务期间的功能性核磁共振成像。在患有幻肢痛的截肢者中,嘴的皮层表征已
延伸到手和手臂的区域。在没有疼痛的截肢者中,被激活的初级体感和运动皮层区域与健康对照组相似(图
未显示)
[170]
411
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
C 纤维
I
II
III
IV
V
VI
至脑干和丘脑
至丘脑
B 脊髓输入
Aδ 纤维
Aδ 纤维
Aβ 纤维
(机械刺激感受器)
C 纤维
A 伤害感受器类型
机械 多觉型
静寂
20.2.1: 伤害感受纤维终止于脊髓背角的不同层。A. 外周伤害受体和寂静性伤害性感受器主要分为 3 类,它们
由炎症和各种化学物质激活。B. 背角 I 层中的神经元通过层 II 中的中间神经元接收来自有髓(Aδ)伤害感受纤
维的直接输入以及来自无髓C伤害感受纤维的直接和间接输入。薄层 V 神经元接收来自大直径有髓鞘 Aβ
械感受纤维的低阈值输入以及来自伤害性 Aδ C 纤维的输入。薄层 V 神经元将树突发送到薄层 IV,在那里它
们与 Aβ 级传入神经的末端接触。II 层中间神经元的轴突末端可以与由 V 层细胞产生的 III 中的树突接触。
Aα 初级传入神经接触腹侧脊髓中的运动神经元和中间神经元(未显示)
[166]
经元接收来自 C 纤维的输入,这些 C 纤维被冷刺激选择性激活。其他类别的 I 神经元以分级方式对无害和有
害的机械刺激作出反应,因此被称为宽动态范围神经元。
薄层 II即明胶质,是一个密集层,包含许多不同类别的局部中间神经元,一些是兴奋性的,另一些是抑
制性的。这些中间神经元中的一些选择性地响应引起疼痛的输入,而另一些则选择性地被引起瘙痒的刺激激活。
薄层 III IV 含有局部中间神经元和脊髓上投射神经元的混合物。许多这些神经元接收来自 Aβ 入纤维的输
入,这些传入纤维对无害的皮肤刺激有反应,例如毛发的偏转和光压。薄层 V 包含对各种有害刺激做出反应并
投射到脑干和丘脑的神经元。如图 20.2.1B 所示,这些神经元接收来自 Aβ Aδ 纤维的直接输入,并且由于它
们的树突延伸到第 II 层,也由 C 纤维伤害受体支配。
薄层 V 中的神经元也接收来自内脏组织中伤害受体的输入。躯体和内脏伤害性输入对单个薄层 V 神经元的
聚合为称为“牵涉痛”的现象提供了一种解释,在这种情况下,内脏组织受伤引起的疼痛被认为起源于身体
面的某个区域。例如,如图 20.2.2 所示,心肌梗塞患者经常报告左臂和胸部疼痛。这种现象的发生是因为单个 V
层神经元 2 个区域接收感觉输入,因此来自该神经元的信号不会通知更高的大脑中枢有关输入源的信息。因
此,大脑经常错误地将疼痛归因于皮肤,这可能是因为皮肤输入占主导地位。对牵涉痛实例的另一种解剖学
释是,伤害性感觉神经元的轴突在周围分支,支配皮肤和内脏目标。
第六层神经元接收来自支配肌肉和关节的大直径初级传入纤维的输入。这些神经元由无害的关节运动激活,
不参与伤害性信息的传递。VII VIII 层(脊髓的中间和腹侧区域)中的许多神经元确实对伤害性刺激有反应。
这些神经元通常具有复杂的响应特性,因为从伤害受体到这些神经元的输入是通过许多中间突触传递的。椎
VII 中的神经元通常对身体任一侧的刺激作出反应,而大多数背角神经元接收单侧输入。因此,人们认为第 VII
层神经元的激活有助于许多疼痛状况的弥散性。
激活脊髓背角神经元的伤害性感觉神经元释放两大类神经递质。无论感觉方式如何,谷氨酸是所有初级
觉神经元的主要神经递质。神经肽作为协同递质被许多带有无髓鞘轴突的伤害受体释放。如图 20.2.3 所示,这
些肽包括肽物质降钙素基因相关肽生长抑素和甘丙肽。如图 20.2.4 所示,谷氨酸储存在小的、电子透明的囊
412
20.2 来自伤害受体的信号被传送到脊髓背角的神经元
476 Part IV / Perception
Figure 20–4 Signals from nociceptors in the viscera can be
felt as “referred pain” elsewhere in the body.
A.Myocardial infarction and angina can be experienced as deep
referred pain in the chest and left arm. The source of the pain
cannot be readily predicted from the site of referred pain.
B.Convergence of visceral and somatic afferent fibers may
account for referred pain. Nociceptive afferent fibers from
the viscera and fibers from specific areas of the skin
converge on the same projection neurons in the dorsal horn.
The brain has no way of knowing the actual site of the
noxious stimulus and mistakenly associates a signal from
a visceral organ with an area of skin. (Adapted, with permission,
from Fields 1987.)
感觉疼痛
的皮肤
B
A
肠道:
损伤部位
前外侧柱轴突
nerves. Its interaction with neurokinin receptors on
dorsal horn neurons elicits slow excitatory postsynap-
tic potentials that prolong the depolarization elicited
by glutamate. Although the physiological actions of
glutamate and neuropeptides on dorsal horn neurons
are different, these transmitters act coordinately to reg-
ulate the firing properties of dorsal horn neurons.
Details of the interaction of neuropeptides with
their receptors on dorsal horn neurons have suggested
strategies for chronic pain regulation. Infusion of sub-
stance P coupled to a neurotoxin into the dorsal horn
of experimental animals results in selective destruction
of neurons that express neurokinin receptors. Animals
treated in this way fail to develop the central sensitization
that is normally associated with peripheral injury. This
method of neuronal ablation is more selective than
traditional surgical interventions such as partial spi-
nal cord transection (anterolateral cordotomy) and is
being considered as a treatment for patients suffering
from otherwise intractable chronic pain.
Hyperalgesia Has Both Peripheral and
Central Origins
Up to this point, we have considered the conveyance of
noxious signals in the normal physiological state. But
the normal process of sensory signaling can be dra-
matically altered when peripheral tissue is damaged,
resulting in an increase in pain sensitivity or hyper-
algesia. This condition can be elicited by sensitizing
peripheral nociceptors through repetitive exposure to
noxious stimuli (Figure 20–7).
The sensitization is triggered by a complex mix of
chemicals released from damaged cells that accumulate
at the site of tissue injury. This cocktail contains pep-
tides and proteins such as bradykinin, substance P, and
nerve growth factor, as well as molecules such as ATP,
histamine, serotonin, prostaglandins, leukotrienes,
and acetylcholine. Many of these chemical mediators
are released from distinct cell types, but together they
act to decrease the threshold of nociceptor activation.
Kandel-Ch20_0470-0495.indd 476 18/01/21 5:54 PM
20.2.2: 来自内脏伤害受体的信号可以在身体其他部位被感知为“牵涉痛”A. 心肌梗塞和心绞痛可表现为胸
部和左臂的深部牵涉痛。从牵涉痛的部位不能很容易地预测疼痛的来源。B. 内脏和躯体传入纤维的汇聚可能
牵涉痛的原因。来自内脏的伤害性传入纤维和来自皮肤特定区域的纤维汇聚在背角的相同投射神经元上。大
无法知道有害刺激的实际位置,并且错误地将来自内脏器官的信号与皮肤区域相关联
[166]
413
20.3 痛觉过敏既有外周起源也有中枢起源
泡中,而肽则被隔离在伤害性感觉神经元中央末端的大的、致密的核心囊泡中。不同的存储位置允许这两类
经递质在不同的生理条件下有选择地释放。
在伤害性感觉神经元释放的神经肽递质中,对神经激肽家族成员肽物质作用进行了最详细的研究。
在组织损伤或周围神经强烈刺激后从伤害性传入神经的中央末端释放。它与背角神经元上的神经激肽受体
相互作用引起缓慢的兴奋性突触后电位,从而延长谷氨酸引起的去极化。尽管谷氨酸和神经肽对背角神经元
生理作用不同,但这些递质协同作用以调节背角神经元的放电特性。
神经肽与其在背角神经元上的受体相互作用的细节为慢性疼痛调节提出了策略。将与神经毒素偶联的
输注到实验动物的背角会导致表达神经激肽受体的神经元的选择性破坏。以这种方式治疗的动物无法产生
常与外周损伤相关的中枢敏化。这种神经元消融方法比部分脊髓横断(前外侧脊髓切开术)等传统外科手术
具选择性,并且被认为是治疗患有其他顽固性慢性疼痛的患者的方法。
20.3 痛觉过敏既有外周起源也有中枢起源
到目前为止,我们已经考虑了正常生理状态下有害信号的传递。但是当外周组织受损时,感觉信号的正
过程会发生显著变化,从而导致疼痛敏感性或痛觉过敏增加。如 20.1.3 所示,这种情况可以通过反复暴露于
伤害性刺激而使外周伤害受体敏感而引发。
致敏作用是由聚集在组织损伤部位的受损细胞释放的复杂化学物质混合物引发的。这种混合物含有肽和
白质,如缓激肽、肽物质和神经生长因子,以及分子,三磷酸腺苷组胺、5-羟色氨前列腺素、白三烯和乙酰
胆碱。这些化学介质中有许多是从不同的细胞类型中释放出来的,但它们共同作用会降低伤害受体激活的阈值。
这些化学物质从何而来,它们究竟有什么作用?组胺在组织损伤后从肥大细胞中释放出来并激活多模态
害受体。脂质大麻素是一种内源性大麻素激动剂,在炎症条件下释放,激活瞬时受体电位香草醛受体 1 通道,
可能引发与炎症相关的疼痛。三磷酸腺、乙酰胆碱 5-羟色氨从受损的内皮细胞和血小板中释放出来;它们
通过触发外周细胞释放前列腺素和缓激肽等化学物质,间接使伤害受体敏感。
缓激肽是最活跃的止痛剂之一。它的效力部分源于这样一个事实,即它直接激活 Aδ C 害受体并增加
附近细胞前列腺素的合成和释放。前列腺素是花生四烯酸的代谢产物,它是通过环氧化酶的活性裂解花生四
酸而产生的(第 14 章)环氧化酶-2 酶优先在外周炎症条件下被诱导,有助于增强疼痛敏感性。前列腺素合
的酶促通路是常用镇痛药物的靶点。阿司匹林和其他非甾体抗炎镇痛药(如布洛芬和萘普生)可有效控制疼痛,
因为它们可阻断环氧化酶的活性,减少前列腺素的合成。
外周伤害受体的活动也会产生炎症的所有主要体征,包括发热(发热)发红(红肿)和肿胀(肿瘤)热和
发红是由外周血管扩张引起的,而肿胀是由血浆外渗引起的,在这个过程中,蛋白质、细胞和液体能够穿透毛细
血管后微静脉。从 C 纤维的外周末端释放神经肽 P 物质降钙素基因相关肽分别引起血浆外渗和血管舒张。如
20.3.1 所示,因为这种形式的炎症取决于神经活动,所以它被称为神经源性炎症。重要的是,由于严重的外周
血管扩张是许多偏头痛的关键触发因素,因此通过清除降钙素基因相关肽来抵消血管扩张的降钙素基因相关
抗体的开发为新的偏头痛治疗提供了巨大的希望。
感觉神经元末梢物质钙素基因相关肽释放也是轴突反射的原因,轴突反射是一种以皮肤损伤附
的血管舒张为特征的生理过程。肽物质的药理学拮抗剂能够阻断人类的神经源性炎症和血管舒张;这一发现
明了如何将伤害性机制的知识应用于改善疼痛的临床治疗。
除了这些小分子和肽外,神经营养素也是疼痛的致病因子。神经生长因子脑源性神经营养因在炎症
疼痛状态下特别活跃。如图 20.3.2 所示,脑源性神经营养因子的合成在许多发炎的外周组织中上调。神经生长
因子中和分子在持续性疼痛的动物模型中是有效的镇痛剂。事实上,神经生长因功能和信号传导的抑制与
氧化酶制剂和阿片类药物一样有效地阻断痛觉。已经报道了几项使神经生长因子体治疗膝骨关节炎的
前途的临床试验,再次证明了基础科学向临床的转化。
是什么导致了背角神经元对伤害受体信号的敏感性增强?如图 20.3.3A 所示,在持续性损伤的情况下,C
维反复放电,背角神经元的反应逐渐增加。如图 20.3.3B 所示,背角神经元兴奋性的逐渐增强被称为“饱和”
认为涉及 N-甲基-D-天冬氨酸型谷氨酸受体。
414
20.3 痛觉过敏既有外周起源也有中枢起源
Chapter 20 / Pain 477
Figure 20–5 Neuropeptides and their receptors in the
superficial dorsal horn of the rat spinal cord.(Images repro-
duced, with permission, from A. Basbaum.)
A.The terminals of unmyelinated primary sensory neurons are
a major source of substance P in the superficial dorsal horn.
Substance P activates the neurokinin-1 (NK1) receptor, which is
expressed by neurons in the superficial dorsal horn, the major-
ity of which are projection neurons.
B.Enkephalin is localized in interneurons and found in the same
region of the dorsal horn as terminals containing substance P.
The μ-opioid receptor, which is targeted by enkephalins, is
expressed by neurons in the superficial dorsal horn and also,
presynaptically, on the terminals of sensory neurons.
A
肽物质
µ
-阿片受体
B 脑啡肽
神经激肽受体
-1
Kandel-Ch20_0470-0495.indd 477 18/01/21 5:54 PM
20.2.3: 大鼠脊髓浅背角的神经肽及其受体。A. 无髓鞘初级感觉神经元的末端是浅表背角中肽物的主要来
源。肽物质激活神经激肽受体-1该受体由浅表背角中的神经元表达,其中大部分是投射神经元。B. 脑啡肽位于
中间神经元中,发现与含有肽物质的末梢位于同一区域。感觉神经元的末梢。
415
20.3 痛觉过敏既有外周起源也有中枢起源
20.2.4: 侧脊髓初级伤害性神经突触末稍的递质存储。A. 背角神经元树突D)上 C 纤维末端有两类
包含不同递质的突触小泡。小的电子透明囊泡含有谷氨酸,而大的致密核囊泡储存神经肽。B. 谷氨酸和肽物
(分别以大金粒和小金粒标记)散布在背 II 感觉神经元末梢的轴浆中。致密核心囊泡还储钙素基因相关
[171]
416
20.3 痛觉过敏既有外周起源也有中枢起源
480 Part IV / Perception
Figure 20–8 Neurogenic inflammation.Injury or tissue
damage releases bradykinin and prostaglandins, which acti-
vate or sensitize nociceptors. Activation of nociceptors leads
to the release of substance P and calcitonin gene–related
peptide (CGRP). Substance P acts on mast cells (light blue)
in the vicinity of sensory endings to evoke degranulation and
the release of histamine, which directly excites nociceptors.
Substance P also produces plasma extravasation and edema,
and CGRP produces dilation of peripheral blood vessels
(leading to reddening of the skin); the resultant inflammation
causes additional liberation of bradykinin. These mechanisms
also occur in healthy tissue, where they contribute to
secondary or spreading hyperalgesia. (Abbreviation: CNS,
central nervous system.)
伤害
前列腺素
缓激肽
前列腺素
缓激肽
至中枢
神经系统
至中枢
神经系统
血浆
至中枢
神经系统
血浆
血浆
C 纤维
(伤害感受器)
降钙素基因相关肽
P 物质
组胺
神经生长因子
损伤部
初始扩散
进一步扩散
前列腺素
缓激肽
Kandel-Ch20_0470-0495.indd 480 18/01/21 5:54 PM
20.3.1: 神经源性炎症。损伤或组织损伤会释放缓激肽和前列腺素,它们会激活伤害受体或使伤害受体敏感。
伤害受体的激活导致肽物质降钙素基因相关肽的释放。肽物质作用于感觉末梢附近的肥大细胞(浅蓝色)
起脱颗粒和组胺释放,直接刺激伤害受体。P 物质还产生血浆外渗和水肿,降钙素基因相关肽产生外周血管扩张
(导致皮肤发红);由此产生的炎症导致缓激肽的额外释放。这些机制也发生在健康组织中,它们会导致继发性
或扩散性痛觉过敏。
417
20.3 痛觉过敏既有外周起源也有中枢起源
Chapter 20 / Pain 481
神经
生长因子
炎症
白细胞介素-1
肥大细胞
神经
生长因子
A
B
C
D
A
外周神经生长因子暴露
B 信号内体的逆行转运
C
脑源性神经营养因子
转录增加
D 脑源性神经营养因子集中释放
脑源性
神经营养因子
细胞核
Figure 20–9 Neurotrophins are pain mediators.Local pro-
duction of inflammatory cytokines such as interleukin-1 (IL-1)
and tumor necrosis factor (TNF) promotes the synthesis and
release of nerve growth factor (NGF) from several cell types
in the periphery. Nerve growth factor binds to TrkA receptors
on primary nociceptive terminals (A), triggering upregulation
in expression of ion channels that increase nociceptor excit-
ability. Retrograde transport of signaling endosomes to the
cell body (B) results in enhanced expression of brain-derived
neurotrophic factor (BDNF) (C), and its release from sensory
terminals in the spinal cord (D) further increases excitability of
dorsal horn neurons.
The sensitization of dorsal horn neurons also
involves recruitment of second-messenger pathways
and activation of protein kinases that have been
implicated in memory storage in other regions of
the central nervous system. One consequence of this
enzymatic cascade is the expression of immediate-
early genes that encode transcription factors such as
c-fos, which are thought to activate effector proteins
that sensitize dorsal horn neurons to sensory inputs.
Most importantly, central sensitization of “pain”
transmission circuitry in the dorsal horn is the pro-
cess that can decrease pain thresholds (allodynia)
and lead to spontaneous pain (ie, ongoing pain in the
absence of peripheral stimulation).
Central sensitization is also a major contributor
to neuropathic pain due to nerve injury. Here again,
there is increased excitability of dorsal horn circuits
mediated by NMDA receptors. There is also loss of
inhibitory controls in the dorsal horn. Under normal
conditions, GABAergic inhibitory interneurons in the
dorsal horn are not only tonically active but are also
turned on by activity of large-diameter, nonnociceptive
Aβ fibers (Figure 20–11A). Peripheral nerve damage
decreases the GABAergic controls, thus exacerbat-
ing the hyperactivity of these nociceptive pathways
(Figure 20–11B). Recent studies also implicate nerve
injury–induced activation of microglia and consequent
reduced GABAergic inhibition in the central sensiti-
zation process (Figures 20–11C and 20–12). Together,
these changes contribute to mechanical allodynia (ie, pain
provoked by normally innocuous mechanical stimula-
tion). Mechanical allodynia can also develop because
of an inappropriate engagement of dorsal horn noci-
ceptive pathway circuits by the Aβ myelinated affer-
ents. In fact, spread of pain (secondary hyperalgesia)
can occur because uninjured Aβ afferents outside of
Kandel-Ch20_0470-0495.indd 481 18/01/21 5:54 PM
肿瘤坏死因子、
脑源性神
经营养因子
20.3.2
: 神经营养素是疼痛介质。
白细胞介素
-1
肿瘤坏死因子
等炎性细胞因子的局部产生促进了外周几种细
胞类型的神经生长因子的合成和释放。神经生长因子与初级伤害受体末梢A上的 TrkA 受体结合,引发离子通
道表达的上调,从而增加伤害受体的兴奋性。信号内体向细胞体的逆行转运B导致脑源性神经营养因子C
的表达增强,并且它从脊髓中的感觉末梢释放(D)进一步增加了背角神经元的兴奋性。
418
20.3 痛觉过敏既有外周起源也有中枢起源
Chapter 20 / Pain 481
神经
生长因子
炎症
白细胞介素-1
肥大细胞
神经
生长因子
A
B
C
D
A
外周神经生长因子暴露
B 信号内体的逆行转运
C
脑源性神经营养因子
转录增加
D 脑源性神经营养因子集中释放
脑源性
神经营养因子
细胞核
Figure 20–9 Neurotrophins are pain mediators.Local pro-
duction of inflammatory cytokines such as interleukin-1 (IL-1)
and tumor necrosis factor (TNF) promotes the synthesis and
release of nerve growth factor (NGF) from several cell types
in the periphery. Nerve growth factor binds to TrkA receptors
on primary nociceptive terminals (A), triggering upregulation
in expression of ion channels that increase nociceptor excit-
ability. Retrograde transport of signaling endosomes to the
cell body (B) results in enhanced expression of brain-derived
neurotrophic factor (BDNF) (C), and its release from sensory
terminals in the spinal cord (D) further increases excitability of
dorsal horn neurons.
The sensitization of dorsal horn neurons also
involves recruitment of second-messenger pathways
and activation of protein kinases that have been
implicated in memory storage in other regions of
the central nervous system. One consequence of this
enzymatic cascade is the expression of immediate-
early genes that encode transcription factors such as
c-fos, which are thought to activate effector proteins
that sensitize dorsal horn neurons to sensory inputs.
Most importantly, central sensitization of “pain”
transmission circuitry in the dorsal horn is the pro-
cess that can decrease pain thresholds (allodynia)
and lead to spontaneous pain (ie, ongoing pain in the
absence of peripheral stimulation).
Central sensitization is also a major contributor
to neuropathic pain due to nerve injury. Here again,
there is increased excitability of dorsal horn circuits
mediated by NMDA receptors. There is also loss of
inhibitory controls in the dorsal horn. Under normal
conditions, GABAergic inhibitory interneurons in the
dorsal horn are not only tonically active but are also
turned on by activity of large-diameter, nonnociceptive
Aβ fibers (Figure 20–11A). Peripheral nerve damage
decreases the GABAergic controls, thus exacerbat-
ing the hyperactivity of these nociceptive pathways
(Figure 20–11B). Recent studies also implicate nerve
injury–induced activation of microglia and consequent
reduced GABAergic inhibition in the central sensiti-
zation process (Figures 20–11C and 20–12). Together,
these changes contribute to mechanical allodynia (ie, pain
provoked by normally innocuous mechanical stimula-
tion). Mechanical allodynia can also develop because
of an inappropriate engagement of dorsal horn noci-
ceptive pathway circuits by the Aβ myelinated affer-
ents. In fact, spread of pain (secondary hyperalgesia)
can occur because uninjured Aβ afferents outside of
Kandel-Ch20_0470-0495.indd 481 18/01/21 5:54 PM
肿瘤坏死因子、
脑源性神
经营养因子
20.3.3: 增强背角神经元兴奋性的机制。A. 大鼠背角神经元对以 1 赫兹频率经皮传递的电刺激的典型反应。
着重复刺激,C 纤维诱发的长潜伏期成分逐渐增加,而 A 纤维诱发的短潜伏期成分保持不变。B. 背角神经元接
收来自 Aδ C 纤维伤害受体的单突触和多突触输入。突触前末端残留 Ca
2+
的升高导致谷氨酸和肽物质(和
钙素基因相关肽未显示)的释放增加。左图:Aδ 纤维激活突触后 AMPA 受体导致快速瞬时膜去极化,从而减
N-甲基-D-天冬氨酸受体的 Mg
2+
阻滞。右图:C 纤维激活突触后 N-甲基-D-天冬氨酸受体和神经激肽受体-1
产生持久的累积去极化。由于 Ca
2+
通过 N-甲基-D-天冬氨酸受体通道和电压敏感 Ca
2+
通道进入,因此背角神经
元中的细胞溶质 Ca
2+
浓度增加。第二信使系统的 Ca
2+
升高和神经激肽受体-1 的激活增强了 N-甲基-D-天冬氨酸
受体的性能。神经激肽受体-1 的激活、累积去极化、细胞溶质 Ca
2+
升高和其他因素调节负责动作电位的电压门
控离子通道的行为,导致兴奋性增强,所有这些都有助于中枢敏化过程。
419
20.4 4 种主要的上行通路将伤害性信息从脊髓传递到大脑
因此,反复暴露于有害刺激会导致背角神经元的反应发生长期变化,其机制类似于大脑中许多回路中突
反应长时程增强的机制。本质上,背角神经元兴奋性的这些长期变化构成了 C 纤维输入状态的“记忆”这种现
象被称为中枢敏化,以区别于背角神经元外周末端的敏化,后者是一种涉及激活前列腺素合成酶通路的过程。
背角神经元的致敏还涉及第二信使通路的募集和与中枢神经系统其他区域的记忆存储有关的蛋白激酶的
活。这种酶促级联的结果之一是编码转录因子(如 c-fos)的早期基因的表达,这些基因被认为可以激活效应蛋
白,使背角神经元对感觉输入敏感。最重要的是,背角“疼痛”传输回路的中枢敏化是可以降低疼痛阈值(异常
性疼痛)并导致自发性疼痛(即在没有外周刺激的情况下持续疼痛)的过程。
中枢敏化也是由于神经损伤引起的神经性疼痛的主要原因。同样,N-甲基-D-天冬氨酸受体介导的背角回路
的兴奋性增加。背角也失去了抑制控制。如图 20.3.4A 所示,在正常情况下,背角中的 γ-氨基丁酸能抑制性中间
神经元不仅具有强直活性,而且还被大直径、非伤害性 Aβ 纤维的活性激活。如图 20.3.4B 所示,外周神经损伤
会降低 γ-氨基丁酸能控制,从而加剧这些伤害性通路的过度活跃。如图 20.3.4C 和图 20.4.1 所示,最近的研究还
表明神经损伤诱导的小胶质细胞激活以及随之而来的中枢致敏过程 γ-氨基丁酸能抑制的减少。这些变化共
导致机械异常性疼痛(即通常无害的机械刺激引起的疼痛)。由于 Aβ 有髓鞘传入神经对背角伤害性通路回路的
不当参与,机械性异常性疼痛也会发生。事实上,可能会发生疼痛扩散(继发性痛觉过敏)因为受伤区域外未
受伤的 Aβ 传入神经会不适当地激活已经发生中枢敏化的背角回路。
20.4 4 种主要的上行通路将伤害性信息从脊髓传递到大脑
4 种主要的上行通路(脊髓丘脑束、脊髓网状束、脊髓旁臂束和脊髓下丘脑束)为产生疼痛的中枢过程提供
感觉信息。
脊髓丘脑束是脊髓中最突出的上行伤害感受通路。它包括位于背角 I V VII 层中的伤害感受特异性、
敏性和宽动态范围神经元的轴突。如图 20.4.2 所示,这些轴突在其起始段附近穿过脊髓中线,并在前外侧白质
中上行,然后终止于丘脑核团。脊髓丘脑束在伤害性信息的传递中起着至关重要的作用。该束起源处的细胞
常具有离散的单侧感受野,这是我们定位疼痛刺激能力的基础。毫不奇怪,电刺激管道足以引起疼痛感;相反,
损伤该束(前外侧脊髓切开术)这种手术通常仅用于晚期癌症患者的顽固性疼痛,可导致损伤对侧身体一侧的
痛觉明显减轻。
脊髓网状束包含椎板 VII VIII 投射神经元的轴突。该束在具有脊髓丘脑束轴突的脊髓前外侧象限中上
行,并终止于网状结构和丘脑。由于脊髓网状束起源处的神经元通常具有较大的、通常是双侧的感受野,因此该
通路更多地涉及弥漫性、定位不佳的疼痛的处理。
脊髓束包 I V 射神的轴突。沿着束传信息认为于疼的情成分。
20.4.2 所示,该束在脊髓的前外侧象限投射到桥脑水平的臂旁核。该通路对中脑网状结构和中脑导水管周围
灰质具有广泛的旁路。臂旁神经元投射到杏仁核,这是边缘系统的一个关键核,它调节情绪状态(第 42 章)
脊髓下丘脑束包含在脊髓 IVVII VIII 层中发现的神经元轴突。这些轴突投射到作为自主控制中心的
下丘脑核团,参与调节伴随疼痛综合症的神经内分泌和心血管反应(第 41 章)
20.5 几个丘脑核将伤害性信息传递给大脑皮层
丘脑包含几个参与伤害性信息中央处理的中继核。丘脑的 2 最重要区域是外侧核群和内侧核群。外侧核
群包括腹后外侧核、腹后内侧核和后/枕核。腹后外侧核和腹后内侧分别通过脊髓丘脑束从背角 I V 层中的伤
害感受特异性神经元和宽动态范围神经元接收输入,并通过三叉神经尾核的三叉神经丘脑束接收输入,背角
三叉神经同系物处理来自口面部区域的伤害感受信息的角。外侧丘脑处理有关受伤精确位置的信息,这些信
通常以急性疼痛的形式传递给意识。与此观点一致,外侧丘脑核中的神经元具有较小的感受野,与突触前脊
神经元的感受野相匹配。
破坏外侧丘脑的脑血管梗塞可产生称为 丘脑综合症(丘脑疼痛)的中枢神经性疼痛病症。患有这种综合症
的患者会经历自发性灼痛以及梗死对侧的异常感觉(称为感觉迟钝)丘脑的电刺激也会导致剧烈疼痛。在一个
420
20.5 几个丘脑核将伤害性信息传递给大脑皮层
Chapter 20 / Pain 483
薄层 V
投射神经元
兴奋性
中间神经元
γ-氨基丁酸
抑制性
中间神经元
γ-氨基丁酸
抑制性
中间神经元
薄层
V
投射神经元
小胶质
细胞
薄层 V
投射神经元
兴奋性
中间神经元
至大脑
神经病理性疼痛
神经病理性疼痛
Aβ 纤维
伤害感受器
薄层
I
投射神经元
A
β 纤维
伤害感受器
伤害感受器
薄层
I
投射神经元
薄层
I
投射神经元
外周神经损伤
外周神经损伤
A 正常疼痛控制
B Aβ−介导的抑制作用丧失
C 小胶质细胞的激活
Figure 20–11 Nerve injury triggers multiple dorsal horn
central sensitization mechanisms that contribute to
neuropathic pain.
A.Under normal conditions, nociceptors engage dorsal
horn pain transmission circuits, via both monosynaptic and
polysynaptic (excitatory) inputs to projection neurons of
laminae I and V that transmit nociceptive information to the
brainstem and thalamus. (See Figure 20–13.) The output of
the projection neurons is regulated by GABAergic inhibitory
interneurons, which can be activated by nonnociceptive,
large-diameter, myelinated Aβ afferent fibers.
B.Peripheral nerve injury can result in a loss of the inhibitory
control exerted by the Aβ afferents, via loss of GABAergic
interneurons, reduced production of GABA, or reduced
expression of GABAergic receptors by the projection
neurons. Pathophysiological sprouting of Aβ afferents may
also permit nonnociceptive inputs to directly engage the
projection neurons (not shown), resulting in the condition of
Aβ-mediated mechanical hypersensitivity/allodynia, a hallmark
of neuropathic pain.
C.Peripheral nerve injury not only activates dorsal horn
neurons directly but also activates microglia, which in turn
release a host of mediators that enhance neuronal excitabil-
ity and reduce the inhibitory controls exerted by GABAergic
interneurons. Thus, targeting the mediators released from
microglia introduces yet another potential approach to the
pharmacotherapy of chronic pain.
Kandel-Ch20_0470-0495.indd 483 18/01/21 5:54 PM
20.3.4: 神经损伤会触发多种背角中枢致敏机制,从而导致神经性疼痛。A. 如图 20.4.2 所示,在正常情况下,
伤害受体通过单突触和多突触(兴奋性)输入到 I 层和 V 层的投射神经元,将伤害感受信息传递到脑干和丘脑,
从而参与背角疼痛传递回路。投射神经元的输出受 γ-氨基丁酸能抑制性中间神经元调节,后者可被非伤害性、
直径、有髓鞘 Aβ 传入纤维激活。B. 外周神经损伤可导致 Aβ 传入神经失去抑制控制,这是通过 γ-氨基丁酸
中间神经元的丢失、γ-氨基丁酸的产生减少或投射神经元对 γ-氨基丁酸能受体的表达减少。Aβ 传入神经的病理
生理发芽也可能允许非伤害性输入直接参与投射神经元(未显示),导 Aβ 介导的机械超敏反应/异常性疼痛,
这是神经性疼痛的标志。C. 周围神经损伤不仅会直接激活背角神经元,还会激活小胶质细胞,小胶质细胞又会
释放大量介质,增强神经元兴奋性并减少 γ-氨基丁酸能中间神经元施加的抑制控制。因此,靶向小胶质细胞
放的介质为慢性疼痛的药物治疗引入了另一种潜在方法。
421
20.5 几个丘脑核将伤害性信息传递给大脑皮层
484 Part IV / Perception
Figure 20–12 Peripheral nerve injury activates microglia in
the dorsal and ventral horns.Schematic drawing and photo-
micrograph illustrate the location where microglia are activated
after peripheral nerve injury. Activation of microglia in the dorsal
horn results from damage (arrow) to the peripheral branch of
primary sensory neurons (orange cells). Microglial activation
around motor neuron cell bodies in the ventral horn occurs
because the same injury damages efferent axons of the motor
neurons (green cells). (Micrograph reproduced, with permis-
sion, from Julia Kuhn.)
小神经胶质细胞
the area of injury can inappropriately activate dorsal
horn circuits that have undergone central sensitization.
Four Major Ascending Pathways Convey
Nociceptive Information From the Spinal Cord
to the Brain
Four major ascending pathways—the spinothalamic,
spinoreticular, spinoparabrachial, and spinohypotha-
lamic tracts—contribute sensory information to the
central processes that generate pain.
The spinothalamic tract is the most prominent
ascending nociceptive pathway in the spinal cord. It
includes the axons of nociceptive-specific, thermosen-
sitive, and wide-dynamic-range neurons in laminae
I and V through VII of the dorsal horn. These axons
cross the midline of the spinal cord near their segment
of origin and ascend in the anterolateral white matter
before terminating in thalamic nuclei (Figure 20–13).
The spinothalamic tract has a crucial role in the trans-
mission of nociceptive information. Cells at the origin
of this tract typically have discrete, unilateral receptive
fields that underlie our ability to localize painful
stimuli. Not surprisingly, electrical stimulation of the
tract is sufficient to elicit the sensation of pain; con-
versely, lesioning this tract (anterolateral cordotomy),
a procedure that is generally only used for intractable
pain in terminal cancer patients, can result in a marked
reduction in pain sensation on the side of the body
contralateral to that of the lesion.
The spinoreticular tract contains the axons of projec-
tion neurons in laminae VII and VIII. This tract ascends
in the anterolateral quadrant of the spinal cord with
spinothalamic tract axons, and terminates in both the
reticular formation and the thalamus. As neurons at
the origin of the spinoreticular tract generally have
large, often bilateral receptive fields, this pathway
has been implicated more in the processing of diffuse,
poorly localized pains.
The spinoparabrachial tract contains the axons of
projection neurons in laminae I and V. Information
transmitted along this tract is thought to contribute
to the affective component of pain. This tract projects
in the anterolateral quadrant of the spinal cord to the
parabrachial nucleus at the level of the pons (Figure
20–13). This pathway has extensive collaterals to the
mesencephalic reticular formation and periaqueductal
gray matter. Parabrachial neurons project to the amyg-
dala, a critical nucleus of the limbic system, which reg-
ulates emotional states (Chapter 42).
The spinohypothalamic tract contains the axons of
neurons found in spinal cord laminae I, V, VII, and VIII.
These axons project to hypothalamic nuclei that serve as
autonomic control centers involved in the regulation of
the neuroendocrine and cardiovascular responses that
accompany pain syndromes (Chapter 41).
Several Thalamic Nuclei Relay Nociceptive
Information to the Cerebral Cortex
The thalamus contains several relay nuclei that partici-
pate in the central processing of nociceptive informa-
tion. Two of the most important regions of the thalamus
are the lateral and medial nuclear groups. The lateral
nuclear group comprises the ventroposterolateral (VPL),
ventroposteromedial (VPM) and posterior/pulvinar
nuclei. The VPL and VPM, respectively, receive inputs
via the spinothalamic tract from nociception-specific
and wide-dynamic-range neurons in laminae I and V
of the dorsal horn and via the trigeminothalamic tract
Kandel-Ch20_0470-0495.indd 484 18/01/21 5:54 PM
20.4.1: 外周神经损伤激活了背角和腹角的小胶质细胞。示意图和显微照片显示了外周神经损伤后小胶质细胞
被激活的位置。背角小胶质细胞的激活是由初级感觉神经元(橙色细胞)外周分支的损伤(箭头)引起的。腹角
运动神经元细胞体周围的小胶质细胞活化是因为同样的损伤会损伤运动神经元的传出轴突(绿色细胞)
422
20.5 几个丘脑核将伤害性信息传递给大脑皮层
Chapter 20 / Pain 485
Figure 20–13 Major ascending pathways that transmit noci-
ceptive information.Sensory discriminative features of the
pain experience are transmitted from the spinal cord to the ven-
troposterolateral thalamus via the spinothalamic tract (brown).
From there, information is transmitted predominantly to the
somatosensory cortex. A second pathway, (the spinoparabra-
chial tract (red), carries information from the spinal cord to the
parabrachial nucleus of the dorsolateral pons. These neurons
in turn target limbic forebrain regions, including the insular and
anterior cingulate cortex, which process emotional features of
the pain experience.
脊髓
脑桥
伤害性
刺激
躯体感觉皮层
(中央后回)
前扣带皮层
丘脑
伤害感受器
岛叶
臂旁核
杏仁核
from the trigeminal nucleus caudalis, the trigeminal
homolog of the dorsal horn that processes nociceptive
information from orofacial regions. The lateral thalamus
processes information about the precise location of an
injury, information usually conveyed to consciousness
as acute pain. Consistent with this view, neurons in
the lateral thalamic nuclei have small receptive fields,
matching those of the presynaptic spinal neurons.
A cerebrovascular infarct that destroys the lat-
eral thalamus can produce a central neuropathic pain
condition called the Dejerine-Roussy (thalamic pain)
syndrome. Patients with this syndrome experience
spontaneous burning pain as well as abnormal sensa-
tions (called dysesthesias) contralateral to the infarct.
Electrical stimulation of the thalamus can also result
in intense pain. In one dramatic clinical case, electri-
cal stimulation of the thalamus rekindled sensations of
angina pectoris that were so realistic that the anesthe-
siologist thought the patient was experiencing a heart
attack. This and other clinical observations suggest
that in chronic neuropathic pain conditions there is a
fundamental change in thalamic and cortical circuitry.
This hypothesis is consistent with studies demonstrat-
ing that the topographic map of the body in the thal-
amus and somatosensory cortex is not fixed, but can
change with use and disuse. Loss of a limb can lead to
shrinking and even disappearance of the cortical rep-
resentation of the limb. Abnormal reorganization likely
contributes to the phantom limb pain (Figure 20–14).
The medial nuclear group of the thalamus com-
prises the medial dorsal and central lateral nucleus of
the thalamus and the intralaminar complex. Its major
input is from neurons in laminae VII and VIII of the
dorsal horn. The pathway to the medial thalamus
was the first spinothalamic projection evident in the
evolution of mammals and is therefore known as the
paleospinothalamic tract. It is also sometimes referred to
as the spinoreticulothalamic tract because it includes
indirect connections through the reticular formation of
the brain stem. The projection from the lateral thala-
mus to the ventroposterior lateral and medial nuclei
is most developed in primates, and thus is termed the
neospinothalamic tract. Many neurons in the medial
thalamus respond optimally to noxious stimuli and
project to many regions of the limbic system, including
the anterior cingulate cortex.
The Perception of Pain Arises From and Can Be
Controlled by Cortical Mechanisms
Anterior Cingulate and Insular Cortex Are
Associated With the Perception of Pain
Imaging studies now show that no single area of the
cortex is responsible for pain perception. Rather, many
regions are activated when an individual experiences
pain. In the somatosensory cortex, neurons typically
have small receptive fields and may not contribute
greatly to the diffuse perception of aches and pains
that characterize most clinical syndromes. The ante-
rior cingulate gyrus and insular cortex also contain
neurons that are activated strongly and selectively by
noxious somatosensory stimuli (Box 20–1).
Kandel-Ch20_0470-0495.indd 485 18/01/21 5:54 PM
20.4.2: 传递伤害感受信息的主要上行通路。疼痛体验的感觉辨别特征通过脊髓丘脑束(棕色)从脊髓传递到
腹后外侧丘脑。从那里,信息主要传输到体感皮层。第二条通路(脊髓旁臂束,以红色显示)将信息从脊髓传递
到背外侧脑桥的臂旁核。这些神经元依次靶向边缘前脑区域,包括岛叶和前扣带皮层,它们处理情绪特征痛
的经历。
423
20.6 疼痛的感知源于皮层机制并受其控制
戏剧性的临床案例中,对丘脑的电刺激重新点燃了心绞痛的感觉,这种感觉非常逼真,以至于麻醉师认为患者正
在经历心脏病发作。这个和其他临床观察表明,在慢性神经性疼痛病症中,丘脑和皮层回路发生了根本性变化。
这一假设与表明丘脑和体感皮层中的身体拓扑映射不是固定的,而是会随着使用和停用而变化的研究是一致的。
失去肢体会导致肢体的皮层表征缩小甚至消失。如图 20.1.4 所示,异常重组可能导致幻肢痛。
丘脑的内侧核群包括丘脑的内侧背核和中央外侧核以及板内复合体。它的主要输入来自背角 VII VIII
中的神经元。通往内侧丘脑的通路是哺乳动物进化中第一个明显的脊髓丘脑投射,因此被称为古脊髓丘脑束。
有时也被称为脊髓网状丘脑束,因为它包括通过脑干网状结构的间接连接。从外侧丘脑到腹后外侧核和内侧
的投射在灵长类动物中最为发达,因此被称为新脊髓丘脑束。内侧丘脑中的许多神经元对伤害性刺激做出最
反应,并投射到边缘系统的许多区域,包括前扣带皮层。
20.6 疼痛的感知源于皮层机制并受其控制
20.6.1 前扣带回和岛叶皮层与疼痛感知有关
影像学研究现在表明,没有哪个皮层区域负责疼痛感知。相反,当一个人经历疼痛时,许多区域会被激活。
在体感皮层中,神经元通常具有较小的感受野,并且可能不会对大多数临床综合症所特有的疼痛和疼痛的弥
性感知做出很大贡献。前扣带回和岛叶皮层也包含神经元,这些神经元会被有害的体感刺激强烈和选择性地
活(文本框 20.1
文本框 20.1 (大脑皮层幻觉疼痛的定位)
如图 20.6.1A 示,桑伯格的幻觉于 1896 年首次出现,是将手放在冷热交替的烤架上后感觉到强烈
且经常疼痛的热量。
一种假说认为,这种错觉是由两类脊髓丘脑束神经元的不同烧烤反应引起的,一类对无害的寒冷敏
感,另一类对有毒的寒冷敏感。这一发现导致了一种基于大脑皮层中央去抑制或揭开面纱过程的疼痛感
知模型。该模型预测了烧烤引起的疼痛和寒冷引起的疼痛之间的感知相似性,这一预测已在心理物理学
上得到验证。疼痛和温度刺激的丘脑皮层整合可能解释了当伤害受体被寒冷激活时所感受到的烧灼感。
位,使
冷、暖、层。层。
20.6.2B 所示,前扣带皮层被桑伯格烤架和有害的热和冷激活,但不被离散的冷热刺激激活。
前扣带回是边缘系统的一部分,参与处理与疼痛相关的情绪状态。岛叶皮层接收来自丘脑和杏仁核的直
投射。岛叶皮层中的神经元处理有关身体内部状态的信息,并有助于疼痛反应的自主成分。重要的是,消融扣带
皮层或从额叶皮层到扣带皮层的通路的神经外科手术可减少疼痛的情感特征,同时不会消除识别损伤强度和
置的能力。患有岛叶皮层病变的患者表现出明显的疼痛无症状综合症。他们认为伤害性刺激是痛苦的,可以
分剧烈疼痛和钝痛,但无法表现出适当的情绪反应。这些观察表明,岛叶皮层是一个整合了疼痛的感觉、情感和
认知成分的区域。
20.6.2 痛觉受伤害性和非伤害性传入纤维活动平衡的调节
脊髓背角的许多投射神经元选择性地对有害输入做出反应,但其他投射神经元接收来自伤害性传入神经
非伤害性传入神经的汇聚输入。将感觉输入汇聚到脊柱投射神经元上调节疼痛处理的念最早出现于 1960
代。
罗纳德 · 梅尔扎克帕特里克 · 沃尔提出,伤害性传入神经和非伤害性传入神经活动的相对平衡可能会影响
疼痛的传递和感知。特别是,他们提出通过激活背角的抑制性中间神经元来激活非伤害性感觉神经元,从而
闭伤害性信号传入传递的“门”而伤害性感觉神经元的激活可以打开该“门”如图 20.6.3 所示,在这个门控理
424
20.6 疼痛的感知源于皮层机制并受其控制
Chapter 20 / Pain 487
Thunberg’s illusion, first demonstrated in 1896, is a
strong, often painful heat felt after placing the hand on a
grill of alternating warm and cool bars (Figure 20–15A).
One hypothesis proposes that this illusory sensa-
tion occurs as a result of differential grill responses of
two classes of spinothalamic tract neurons, one sensitive
to innocuous and another to noxious cold. This finding
has led to a model of pain perception based on a central
disinhibition or unmasking process in the cerebral cor-
tex. The model predicts perceptual similarities between
grill-evoked and cold-evoked pain, a prediction that
has been verified psychophysically. The thalamocortical
integration of pain and temperature stimuli may explain
the burning sensation felt when nociceptors are acti-
vated by cold.
To identify the anatomical site of the unmasking
phenomenon described above, positron emission tomog-
raphy (PET) was used to compare the cortical areas acti-
vated by Thunberg’s grill with those activated by cool,
warm, noxious cold, and noxious heat stimuli separately.
All thermal stimuli activate the insula and somatosen-
sory cortices. The anterior cingulate cortex is activated by
Thunberg’s grill and by noxious heat and cold, but not by
discrete warm and cool stimuli (Figure 20–15B).
Box 20–1 Localizing Illusory Pain in the Cerebral Cortex
Figure 20–15A Thunberg’s thermal grill. The stimulus
surface (20 × 14 cm) is made of 15 sterling silver bars,
each 1 cm wide, set approximately 3 mm apart. Under-
neath each bar are three longitudinally spaced thermoelec-
tric (Peltier) elements (1 cm
2
), and on top of each bar is a
thermocouple. Alternate (even- and odd-numbered) bars
can be controlled independently. (Adapted, with permis-
sion, from Craig and Bushnell 1994. Copyright © 1994
AAAS.)
Figure 20–15B Cortical areas
activated by Thunberg’s grill. The
anterior cingulate and insula regions
of the cerebral cortex are activated
when the hand is placed on the grill
but not when warm and cool stimuli
are applied separately. (Reproduced,
with permission, from Craig AD,
Reiman EM, Evans A, et al. 1996.
Functional imaging of an illusion of
pain. Nature 384:258–260. Copyright
© 1996 Springer Nature.)
A
Anterior cingulate
B
Insula
Noxious
cold
Grill
(cool and warm)
Noxious
heat
WarmCool
Kandel-Ch20_0470-0495.indd 487 18/01/21 5:54 PM
20.6.1: 桑伯格的烤架。刺激表面20 × 14 厘米)由 15 根纯银条制成,每条宽 1 厘米,间隔约 3 毫米。在每
个棒的下面是 3 个纵向间隔的热电(帕尔贴元件1cm
2
在每个棒上是一个热电偶。交替(偶数和奇数)
可以独立控制
[172]
Chapter 20 / Pain 487
Thunberg’s illusion, first demonstrated in 1896, is a
strong, often painful heat felt after placing the hand on a
grill of alternating warm and cool bars (Figure 20–15A).
One hypothesis proposes that this illusory sensa-
tion occurs as a result of differential grill responses of
two classes of spinothalamic tract neurons, one sensitive
to innocuous and another to noxious cold. This finding
has led to a model of pain perception based on a central
disinhibition or unmasking process in the cerebral cor-
tex. The model predicts perceptual similarities between
grill-evoked and cold-evoked pain, a prediction that
has been verified psychophysically. The thalamocortical
integration of pain and temperature stimuli may explain
the burning sensation felt when nociceptors are acti-
vated by cold.
To identify the anatomical site of the unmasking
phenomenon described above, positron emission tomog-
raphy (PET) was used to compare the cortical areas acti-
vated by Thunberg’s grill with those activated by cool,
warm, noxious cold, and noxious heat stimuli separately.
All thermal stimuli activate the insula and somatosen-
sory cortices. The anterior cingulate cortex is activated by
Thunberg’s grill and by noxious heat and cold, but not by
discrete warm and cool stimuli (Figure 20–15B).
Box 20–1 Localizing Illusory Pain in the Cerebral Cortex
Figure 20–15A Thunberg’s thermal grill. The stimulus
surface (20 × 14 cm) is made of 15 sterling silver bars,
each 1 cm wide, set approximately 3 mm apart. Under-
neath each bar are three longitudinally spaced thermoelec-
tric (Peltier) elements (1 cm
2
), and on top of each bar is a
thermocouple. Alternate (even- and odd-numbered) bars
can be controlled independently. (Adapted, with permis-
sion, from Craig and Bushnell 1994. Copyright © 1994
AAAS.)
Figure 20–15B Cortical areas
activated by Thunberg’s grill. The
anterior cingulate and insula regions
of the cerebral cortex are activated
when the hand is placed on the grill
but not when warm and cool stimuli
are applied separately. (Reproduced,
with permission, from Craig AD,
Reiman EM, Evans A, et al. 1996.
Functional imaging of an illusion of
pain. Nature 384:258–260. Copyright
© 1996 Springer Nature.)
A
前扣带回
B
脑岛
寒毒 烤架
(凉爽而温暖)
热毒
温暖凉爽
Kandel-Ch20_0470-0495.indd 487 18/01/21 5:54 PM
20.6.2: 桑伯格烤架激活的皮层区域。当手放在烤架上时,大脑皮层的前扣带和脑岛区域会被激活,但当分别
施加温暖和凉爽的刺激时,则不会被激活。
425
20.6 疼痛的感知源于皮层机制并受其控制
论的原始和最简单的形式中,大纤维和小纤维之间的相互作用发生在脊髓背角投射神经元的第一个可能会聚点。
我们现在知道,这种相互作用也可以发生在许多脊髓上中继中心。
Chapter 20 / Pain 485
Figure 20–13 Major ascending pathways that transmit noci-
ceptive information.Sensory discriminative features of the
pain experience are transmitted from the spinal cord to the ven-
troposterolateral thalamus via the spinothalamic tract (brown).
From there, information is transmitted predominantly to the
somatosensory cortex. A second pathway, (the spinoparabra-
chial tract (red), carries information from the spinal cord to the
parabrachial nucleus of the dorsolateral pons. These neurons
in turn target limbic forebrain regions, including the insular and
anterior cingulate cortex, which process emotional features of
the pain experience.
脊髓
脑桥
伤害性
刺激
躯体感觉皮层
(中央后回)
前扣带皮层
丘脑
伤害感受器
岛叶
臂旁核
杏仁核
from the trigeminal nucleus caudalis, the trigeminal
homolog of the dorsal horn that processes nociceptive
information from orofacial regions. The lateral thalamus
processes information about the precise location of an
injury, information usually conveyed to consciousness
as acute pain. Consistent with this view, neurons in
the lateral thalamic nuclei have small receptive fields,
matching those of the presynaptic spinal neurons.
A cerebrovascular infarct that destroys the lat-
eral thalamus can produce a central neuropathic pain
condition called the Dejerine-Roussy (thalamic pain)
syndrome. Patients with this syndrome experience
spontaneous burning pain as well as abnormal sensa-
tions (called dysesthesias) contralateral to the infarct.
Electrical stimulation of the thalamus can also result
in intense pain. In one dramatic clinical case, electri-
cal stimulation of the thalamus rekindled sensations of
angina pectoris that were so realistic that the anesthe-
siologist thought the patient was experiencing a heart
attack. This and other clinical observations suggest
that in chronic neuropathic pain conditions there is a
fundamental change in thalamic and cortical circuitry.
This hypothesis is consistent with studies demonstrat-
ing that the topographic map of the body in the thal-
amus and somatosensory cortex is not fixed, but can
change with use and disuse. Loss of a limb can lead to
shrinking and even disappearance of the cortical rep-
resentation of the limb. Abnormal reorganization likely
contributes to the phantom limb pain (Figure 20–14).
The medial nuclear group of the thalamus com-
prises the medial dorsal and central lateral nucleus of
the thalamus and the intralaminar complex. Its major
input is from neurons in laminae VII and VIII of the
dorsal horn. The pathway to the medial thalamus
was the first spinothalamic projection evident in the
evolution of mammals and is therefore known as the
paleospinothalamic tract. It is also sometimes referred to
as the spinoreticulothalamic tract because it includes
indirect connections through the reticular formation of
the brain stem. The projection from the lateral thala-
mus to the ventroposterior lateral and medial nuclei
is most developed in primates, and thus is termed the
neospinothalamic tract. Many neurons in the medial
thalamus respond optimally to noxious stimuli and
project to many regions of the limbic system, including
the anterior cingulate cortex.
The Perception of Pain Arises From and Can Be
Controlled by Cortical Mechanisms
Anterior Cingulate and Insular Cortex Are
Associated With the Perception of Pain
Imaging studies now show that no single area of the
cortex is responsible for pain perception. Rather, many
regions are activated when an individual experiences
pain. In the somatosensory cortex, neurons typically
have small receptive fields and may not contribute
greatly to the diffuse perception of aches and pains
that characterize most clinical syndromes. The ante-
rior cingulate gyrus and insular cortex also contain
neurons that are activated strongly and selectively by
noxious somatosensory stimuli (Box 20–1).
Kandel-Ch20_0470-0495.indd 485 18/01/21 5:54 PM
20.6.3: 疼痛的闸门控制理论。门控假说在 1960 代提出,以解释低阈值初级传入纤维的激活可以减轻疼痛
这一事实。该假设侧重于脊髓背角神经元的相互作用:伤害性C和非伤害性Aa感觉神经元、投射神经元
和抑制性中间神经元。在模型的原始版本中,如图所示,投射神经元被两类感觉神经元兴奋,并被浅表背角中的
中间神经元抑制。这两类感觉纤维也终止于抑制性中间神经元;C 纤维间接抑制中间神经元,从而增加投射神经
元的活动(从而“打开门”,而 Aβ 纤维刺激中间神经元,从而抑制投射神经元的输出(并“关闭门”
不同感觉方式的融合概念为设计新的疼痛疗法提供了重要基础。从最广泛的意义上看,脊柱或脊柱上部
的高阈值和低阈值输入的融合为关于疼痛感知的几项经验观察提供了合理的解释。手被锤击或烧伤后的抖动
一种反射行为,可以通过激活抑制有害刺激信息传递的大直径传入纤维来减轻疼痛。
融合的想法也有助于促进使用经皮神经电刺和脊髓刺激来缓解疼痛。使经皮神经电刺激放置在外
位置的刺激电极会激活大直径传入纤维,这些纤维支配重叠区域,但也围绕受伤和疼痛区域。疼痛减轻的身
区域映射到脊髓的那些区段,来自该身体区域的伤害感受和非伤害感受传入终止。这符合直觉:您不会通过
动左腿来减轻右臂的疼痛。
426
20.7 阿片肽有助于内源性疼痛控制
20.6.3 大脑的电刺激产生镇痛
几个内源性疼痛调节位点位于大脑中。抑制伤害感受的一种有效方法包括刺激导水管周围灰质,即围绕
三脑室和大脑导水管的中脑区域。在实验动物中,刺激该区域会引起深度和选择性镇痛。这种刺激产生的镇
作用具有显著的特异性;动物仍然会对对疼痛不敏感的身体区域的触摸、压力和温度做出反应。刺激诱发镇
已被证明是在有限数量的人类疼痛条件下缓解疼痛的有效方法。
刺激导水管周围灰质会阻断通常由有害刺激引起的脊髓介导的退缩反射。导水管周围灰质中的神经元很
直接投射到脊髓的背角。大多数与延髓前腹侧神经元建立兴奋性联系,包括中线区域称为中缝大核的 5-羟色氨
能神经元。如 20.6.4 所示,这些 5-羟色氨能神经元的轴突通过外侧索的背侧区域投射到脊髓,在那里它们与
背角 III V 层中的神经元形成抑制性连接。因此,刺激延髓前腹侧会抑制许多类背角神经元的放电,包括向
大脑传递传入伤害性信号的主要上行通路的投射神经元。
第二个主要的单胺能下行系统也可以抑制背角伤害感受神经元的活动。如图 20.6.4 示,这种去甲肾上腺
素能系统起源于蓝斑和延髓和脑桥的其他核团。通过直接和间接的突触作用,这些投射抑制了背角 I V 层中
的神经元。
20.7 阿片肽有助于内源性疼痛控制
自公元前 3300 年苏美尔人发现罂粟以来,该植物的活性成分,如吗啡和可待因等阿片类药物,已被公认为
强效镇痛剂。在过去的 20 年里,我们已经开始了解许多阿片类药物发挥镇痛作用的分子机制和神经回路。此外,
我们已经认识到,参与刺激产生的镇痛和阿片类镇痛的神经网络密切相关。
2 关键发现导致了这些进步。首先是认识到吗啡和其他阿片类药物与脊髓和大脑神经元上的特定受体
互作用。第二个是分离在这些受体上具有类鸦片活性的内源性神经肽。阿片拮抗剂纳洛酮阻断刺激产生的镇
作用的观察结果提供了大脑含有内源性阿片样物质的第一个线索。
20.7.1 内源性阿片肽及其受体分布在疼痛调节系统中
阿片受体分为四大类:µδκ 孤啡肽编码每一种受体类型的基因构成了三磷酸鸟苷结合蛋白偶联受体
1 个亚家族。µ 受体特别多样化;已经鉴定出许多 µ 受体亚型,其中许多具有不同的表达模式。这一发现促使
人们寻找针对特定亚型的镇痛药。
阿片受体最初是根据不同激动剂化合物的结合亲和力定义的。吗啡和其他阿片类生物碱 µ 体的有效激
动剂,镇痛剂的效力与其与 µ 受体结合的亲和力之间存在紧密相关性。µ 受体基因失活的小鼠对吗啡和其他
片类激动剂不敏感。许多阿片类拮抗剂药物,如纳洛酮,也与 µ 受体结合并与吗啡竞争受体占用而不激活受体
信号传导。
µ 受体高度集中在脊髓浅表背角、腹侧延髓和导水管周围灰质(调节疼痛的重要解剖部位)。然而,与其他
类别的阿片受体一样,它们也存在于中枢和周围神经系统的许多其他部位。它们的广泛分布解释了为什么全
给药的吗啡会影响除疼痛感知之外的许多生理过程。
阿片受体的发现及其在中枢和外周神经系统中神经元的表达导致了四大类内源性阿片肽的定义,每一种
与一类特定的阿片受体相互作用(表 20.1
3 个类别(脑啡肽、β-内啡肽和强啡肽)具有最好的特征。如图 20.7.1 所示,这些阿片肽由大的多肽前体通
过酶促裂解形成,并由不同的基因编码。尽管氨基酸序列不同,但每个都包含 Tyr-Gly-Gly-Phe 序列。β-内啡肽是
一种前体的裂解产物,它也能产生活性肽促肾上腺皮质激素β-内啡肽和促肾上腺皮层激素均由垂体细胞合成,
并在应激反应下释放到血液中。强啡肽来源于强啡肽基因的多蛋白产物。
4 类阿片肽的成员广泛分布在中枢神经系统中,各个肽位于与伤害性信息的处理或调节相关的位点。含有脑
啡肽和强啡肽的神经元细胞体和轴突末端存在于脊髓的背角,特别是 I II 层,以及延髓头端腹侧和导水管周
围灰质中。合成 β-内啡肽的神经元主要局限于下丘脑;它们的轴突终止于导水管周围灰质和脑干中的去甲肾上
腺素能神经元。孤啡肽似乎参与广泛的其他生理功能。
427
20.7 阿片肽有助于内源性疼痛控制
Chapter 20 / Pain 489
medulla thus inhibits the firing of many classes of dor-
sal horn neurons, including projection neurons of the
major ascending pathways that convey afferent nocic-
eptive signals to the brain.
A second major monoaminergic descending sys-
tem can also suppress the activity of nociceptive neu-
rons in the dorsal horn. This noradrenergic system
Figure 20–17 Descending monoaminergic pathways regu-
late nociceptive relay neurons in the spinal cord.A seroton-
ergic pathway arises in the nucleus raphe magnus and projects
through the dorsolateral funiculus to the dorsal horn of the
spinal cord. A noradrenergic system arises in the locus ceruleus
and other nuclei in the pons and medulla. (See Figure 40–11A
for the locations and projections of monoaminergic neurons.)
In the spinal cord, these descending pathways inhibit nocicep-
tive projection neurons through direct connections as well as
through interneurons in the superficial layers of the dorsal horn.
Both the serotonergic nucleus raphe magnus and noradrener-
gic nuclei receive input from neurons in the periaqueductal gray
region. Sites of opioid peptide expression and actions of exog-
enously administered opioids are shown.
中缝大核
血清素
通路
蓝斑
中脑导水管
周围灰质
阿片镇痛部位
镇痛阻断部位
(使用纳洛酮)
去甲肾上腺素能
通路
中脑
脑桥
延髓
脊髓
originates in the locus ceruleus and other nuclei of the
medulla and pons (Figure 20–17). Through direct and
indirect synaptic actions, these projections inhibit neu-
rons in laminae I and V of the dorsal horn.
Opioid Peptides Contribute to Endogenous
Pain Control
Since discovery of the opium poppy by the Sumerians
in 3300 BC, the plant’s active ingredients, opiates such
as morphine and codeine, have been recognized as
powerful analgesic agents. Over the past two decades,
we have begun to understand many of the molecular
mechanisms and neural circuits through which opi-
ates exert their analgesic actions. In addition, we have
come to realize that the neural networks involved in
stimulation-produced and opiate-induced analgesia
are intimately related.
Two key discoveries led to these advances. The
first was the recognition that morphine and other opi-
ates interact with specific receptors on neurons in the
spinal cord and brain. The second was the isolation
of endogenous neuropeptides with opiate-like activi-
ties at these receptors. The observation that the opiate
antagonist, naloxone, blocks stimulation-produced
analgesia provided the first clue that the brain contains
endogenous opioids.
Endogenous Opioid Peptides and Their Receptors
Are Distributed in Pain-Modulatory Systems
Opioid receptors fall into four major classes: mu (μ),
delta (δ), kappa (κ), and orphanin FQ. The genes
encoding each of these receptor types constitute a sub-
family of G protein–coupled receptors. The μ receptors
are particularly diverse; numerous μ receptor isoforms
have been identified, many with different patterns of
expression. This finding has prompted a search for
analgesic drugs that target specific isoforms.
The opioid receptors were originally defined on
the basis of the binding affinity of different agonist
compounds. Morphine and other opioid alkaloids are
potent agonists at μ receptors, and there is a tight cor-
relation between the potency of an analgesic and its
affinity of binding to μ receptors. Mice in which the
gene for the μ receptor has been inactivated are insen-
sitive to morphine and other opiate agonists. Many
opiate antagonist drugs, such as naloxone, also bind to
the μ receptor and compete with morphine for receptor
occupancy without activating receptor signaling.
The μ receptors are highly concentrated in the
superficial dorsal horn of the spinal cord, the ventral
Kandel-Ch20_0470-0495.indd 489 18/01/21 5:55 PM
20.6.4: 下行单胺能通路调节脊髓中的伤害性中继神经元。5-羟色胺能通路出现在中缝大核中,并通过背外侧
索投射到脊髓的背角。去甲肾上腺素能系统出现在脑桥和延髓的和其他核团中(有关单胺能神经元的位
和投射,请参见图 40.4.1A。在脊髓中,这些下行通路通过直接连接以及通过背角表层的中间神经元抑制伤
性投射神经元。5-羟色胺能中缝大核和去甲肾上腺素能核都接收来自导水管周围灰质神经元的输入。显示了
片样肽表达的位点和外源性阿片样物质的作用。
428
20.7 阿片肽有助于内源性疼痛控制
20.1: 四大类内源性阿片肽
前肽 优先受体
前阿黑皮素 β-内啡肽 µ/δ
内吗啡肽-1 µ
内吗啡肽-2 µ
脑啡肽原 甲硫氨酸脑啡肽 δ
亮氨酸脑啡肽 δ
前强啡肽 强啡肽 A κ
强啡肽 B κ
前孤啡肽 孤啡肽 B 孤儿受体
Chapter 20 / Pain 491
B 蛋白水解加工的阿片肽
甲硫氨酸脑啡肽
亮氨酸脑啡肽
β-内啡肽
强啡肽
α-新内啡肽
孤啡肽
氨基酸序列
Tyr Gly Gly Phe Met OH
Tyr Gly Gly Phe Leu OH
β-END
M
D
N
O
L
Tyr Gly Gly Phe Thr Gly Ala Arg Lys Ser Ala Arg Lys
Leu Ala Asn Gln
Tyr Gly Gly Phe Leu Arg Lys Tyr Pro Lys
Tyr Gly Gly Phe Leu Arg Arg Ile Arg Pro Lys Leu Lys
Trp Asp Asn Gln OH
Tyr Gly Gly Phe Met Thr Ser Glu Lys Ser Gln Thr Pro
Leu Val Thr Leu Phe Lys Asn Ala Ile Val Lys Asn Ala
His Lys Gly Gln OH
NDD
MM MM
M
M
L
强啡肽原
γ
MSH
γ
-LPH
β-END
α
MSH
CLIP
O
前孤啡肽
A 前体蛋白
前脑啡肽
前前阿黑皮素
Figure 20–18 Four families of endogenous opioid peptides
arise from large precursor polyproteins.
A.Proteolytic enzymes cleave each of the precursor proteins
to generate shorter, biologically active peptides, some of
which are shown in this diagram. The proenkephalin precur-
sor protein contains multiple copies of methionine-enkephalin
(M), leucine-enkephalin (L), and several extended enkephalins.
Proopiomelanocortin (POMC) contains β-endorphin (β-END,
melanocyte-stimulating hormone (MSH), adrenocorticotropic
hormone (ACTH), and corticotropin-like intermediate-lobe pep-
tide (CLIP). The prodynorphin precursor can produce dynorphin
(D) and α-neoendorphin (N). The pro-orphanin precursor con-
tains the orphanin FQ peptide (O), also called nociceptin. The
black domains indicate a signal peptide.
B.Amino acid sequences of proteolytically processed bioactive
peptides. The amino acid residues shown in bold type mediate
interaction with opioid receptors. (Adapted, with permission,
from Fields 1987.)
entry into the sensory nerve terminal (Figure 20–19B).
This effect in turn inhibits the release of neurotransmit-
ter and thereby decreases activation of postsynaptic
dorsal horn neurons.
The wide distribution of opioid receptors within
the brain and periphery accounts for the many side
effects produced by opiates. Activation of opioid
receptors expressed by muscles of the bowel and anal
sphincter results in constipation. Similarly, opioid
receptor–mediated inhibition of neuronal activity in
the nucleus of the solitary tract underlies the respira-
tory depression and cardiovascular side effects. For
this reason, direct spinal administration of opiates
has significant advantages. Morphine injected into
the cerebrospinal fluid of the spinal cord subarach-
noid space interacts with opioid receptors in the dor-
sal horn to elicit a profound and prolonged analgesia.
Spinal administration of morphine is now commonly
used in the treatment of postoperative pain, nota-
bly the pain associated with cesarean section during
childbirth. In addition to producing prolonged anal-
gesia, intrathecal morphine has fewer side effects
because the drug does not diffuse far from its site of
injection. Continuous local infusion of morphine to
the spinal cord has also been used for the treatment of
certain cancer pains.
Kandel-Ch20_0470-0495.indd 491 18/01/21 5:55 PM
20.7.1: 四个内源性阿片肽家族来自大的前体多蛋白。A. 蛋白水解酶切割每个前体蛋白以生成较短的生物活性
肽,其中一些显示在该图中。脑啡肽原前体蛋白包含多个拷贝的甲硫氨酸脑啡肽亮氨酸-脑啡肽L和几种扩
展的脑啡肽。前阿黑皮素含有 β-内啡肽β-END黑素细胞刺激素促肾上腺皮质激素促皮质激素样中间肽
前炔诺啡前体可以产生强啡肽(D)和 α-新内啡肽(N。原孤啡肽前体含有孤啡肽O,也称为伤害肽。黑色
结构域表示信号肽。B. 蛋白水解加工的生物活性肽的氨基酸序列。氨基酸残基以粗体显示类型介导与阿片受体
的相互作用
[166]
429
20.8 亮点
20.7.2 吗啡通过激活阿片受体来控制疼痛
将低剂量的吗啡、其他阿片类药物或阿片肽直接显微注射到大鼠大脑的特定区域会产生强大的镇痛作用。
水管周围灰质是最敏感的部位之一,但将吗啡局部给药到其他区域,包括脊髓,也会产生强大的镇痛作用。
如图 20.6.4 所示,可通过将阿片拮抗剂纳洛酮注射到导水管周围灰质区域或中缝大核中来阻断吗啡诱导的
全身镇痛。此外,脊髓背外侧索的双侧横切可阻断中枢给药吗啡诱导的镇痛作用。因此,吗啡的中枢镇痛作用涉
及到脊髓下行通路的激活,与介导脑电刺激和吗啡产生的镇痛作用的下行通路相同。
与其他地方一样,在脊髓中,吗啡通过模仿内源性阿片肽的作用发挥作用。如图 20.7.2A 所示,脊髓浅背角
包含表达脑啡肽和强啡肽的中间神经元,这些神经元的末端靠近伤害性感觉神经元和脊髓投射神经元形成的
触。此外,µδ κ 受体位于伤害性感觉神经元的末端以及接收传入伤害性输入的背角神经元的树突上,因此
将内源性阿片肽置于调节感觉输入的战略位置。如图 20.1.1 示,介导缓慢持续性疼痛或“第二次疼痛” C
纤维伤害受体比介导快速和急性疼痛或“第一次疼痛” Aδ 伤害受体具有更多的 µ 受体。这可能有助于解释为
什么吗啡在治疗持续性疼痛而不是急性疼痛方面更有效。
阿片类药物(阿片类药物和阿片类肽)通过 2 种主要机制调节背角突触处的伤害感受传递。首先,它们增
加了背角神经元的膜 K
+
电导,使神经元超极化并增加了它们的激活阈值。其次,如图 20.7.2B 所示,通过与突
触前感觉神经末梢上的受体结合,阿片类药物阻断电压门控Ca
2+
通道,从而减少Ca
2+
进入感觉神经末梢。这种
作用反过来会抑制神经递质的释放,从而减少突触后背角神经元的激活。
阿片受体在大脑和外周的广泛分布是阿片类药物产生的许多副作用的原因。由肠和肛门括约肌的肌肉表
的阿片受体的激活导致便秘。同样,阿片受体介导的孤束核神经元活动抑制是呼吸抑制和心血管副作用的基础。
出于这个原因,阿片类药物的直接脊髓给药具有显著的优势。注入脊髓蛛网膜下腔的脑脊液中的吗啡与背角
的阿片受体相互作用,引起深度和长时间的镇痛。吗啡的脊柱给药现在常用于治疗术后疼痛,尤其是分娩时
剖宫产相关的疼痛。除了产生延长的镇痛作用外,鞘内注射吗啡的副作用较少,因为药物不会扩散到远离注
部位的地方。向脊髓连续局部输注吗啡也已用于治疗某些癌症疼痛。
阿片类药物还作用于大脑皮层的受体。例如,有证据表明阿片类药物可以通过前扣带回的作用影响疼痛
验的情感成分。最有趣的是,有相当多的证据表明安慰剂镇痛涉及内啡肽释放,并且可以被纳洛酮逆转。这一发
现强调,对安慰剂的反应并不表明疼痛是某种想象出来的。此外,安慰剂镇痛是任何止痛药(包括吗啡)整体镇
痛作用的组成部分,前提是患者认为治疗有效。另一方面,其他一些减轻疼痛的心理干预,即催眠,似乎并不涉
及内啡肽的释放。
20.7.3 对阿片类药物的耐受和依赖是截然不同的现象
长期使用吗啡会引发重大问题,最显著的是耐受性和心理依赖性(成瘾)(第 43 章)重复使用吗啡来缓解
疼痛会导致患者对药物的镇痛作用产生抵抗力,因此需要逐渐增加药物剂量才能达到相同的治疗效果。一种
论认为,耐受性是阿片受体与其三磷酸鸟苷结合蛋白转导物解偶联的结果。然而,由于纳洛酮与 µ -片受体的
结合可以在耐受受试者中引发戒断症状,因此阿片受体似乎在耐受状态下仍然活跃。因此,耐受性也可能反
了细胞对阿片受体激活的反应,这种反应抵消了阿片剂的作用并重置了系统。随之而来的是,当阿片类药物
然被移除或纳洛酮被给药时,这种补偿反应就会暴露出来,从而导致戒断反应。
这种生理耐受性与依赖/成瘾不同,依赖/成瘾是一种对药物的心理渴望,与药物滥用有关,并导致阿片类药
物使用障碍。鉴于与阿片类药物相关的死亡人数惊人地增加,无论是由于处方阿片类药物的滥用和过量服用
是由于一系列社会经济因素,进一步研究有助于发展和区分耐受性和成瘾的机制是必不可少的。毫无疑问,
啡和其他阿片类药物在控制术后疼痛方面非常有用。它们是否对非癌症患者的慢性疼痛管理同样有效仍存在
议,需要进一步研究。
430
20.8 亮点
492 Part IV / Perception
Figure 20–19 Local interneurons in the spinal cord integrate
descending and afferent nociceptive pathways.
A.Nociceptive afferent fibers, local interneurons, and descend-
ing fibers interconnect in the dorsal horn of the spinal cord (see
also Figure 20–3B). Nociceptive fibers terminate on second-
order projection neurons. Local GABAergic and enkephalin-
containing inhibitory interneurons exert both pre- and
postsynaptic inhibitory actions at these synapses. Serotonergic
and noradrenergic neurons in the brain stem activate the local
interneurons and also suppress the activity of the projection
neurons. Loss of these inhibitory controls contributes to
ongoing pain and pain hypersensitivity.
B.Regulation of nociceptive signals at dorsal horn synapses.
1. Activation of a nociceptor leads to the release of
glutamate and neuropeptides from the primary sensory
neuron, producing an excitatory postsynaptic potential in the
projection neuron. 2. Opiates decrease the duration of the
postsynaptic potential, probably by reducing Ca
2+
influx, and
thus decrease the release of transmitter from the primary
sensory terminals. In addition, opiates hyperpolarize the
dorsal horn neurons by activating a K
+
conductance and thus
decrease the amplitude of the postsynaptic potential in the
dorsal horn neuron.
去甲肾上腺素
血清素
伤害感受器
感觉神经元
投射神经元
吗啡
吗啡
控制
无感觉输入
感觉输入
神经肽
Ca
2+
谷氨酸
1 单独的感觉输入
2 感觉输入 + 鸦片制剂/鸦片
控制
Ca
2+
脑啡肽
脑啡肽
无感觉输入
+ 鸦片制剂
感觉输入
+ 鸦片制剂
脑啡肽
脑啡肽
控制
B 阿片类药物对伤害感受器信号传递的影响
伤害感受器
A 背角伤害感受器回路
鸦片制剂
控制
投射神经元
脑啡肽
中间神经元
至更高的中心
+
+
Kandel-Ch20_0470-0495.indd 492 18/01/21 5:55 PM
20.7.2: 脊髓中的局部中间神经元整合了下行和传入伤害性通路。A. 伤害性传入纤维、局部中间神经元和下行
纤维在脊髓的背角相互连接(另请参见图 20.2.1B伤害性纤维终止于二阶投射神经元。局部γ-氨基丁酸能和含
脑啡肽的抑制性中间神经元在这些突触处发挥突触前和突触后抑制作用。脑干中的 5-羟色能和去甲肾上腺素
能神经元激活局部中间神经元并抑制投射神经元的活动。失去这些抑制控制会导致持续的疼痛和疼痛超敏反应。
B. 背角突触伤害性信号的调节。1. 伤害受体的激活导致初级感觉神经元释放谷氨酸和神经肽,从而在投射神经
元中产生兴奋性突触后电位。2. 阿片类药物减少突触后电位的持续时间,可能是通过减少Ca
2+
流入,从而减少
从初级感觉终端释放递质。此外,阿片类药物通过激活 K
+
电导使背角神经元超极化,从而降低背角神经元突触
后电位的振幅。
431
20.8 亮点
20.8 亮点
1. 外周伤害性轴突,细胞体位于背根神经节,包括小直径无髓鞘C和有髓鞘Aδ传入神经。较大直径
Aβ 传入神经仅对无害刺激有反应,但在受伤后可激活中枢神经系统疼痛回路。
2. 所有伤害受体都使用谷氨酸作为兴奋性神经递质;许多还表达兴奋性神经肽协同递质,例肽物质
钙素基因相关肽
3. 伤害受体还通过它们对温度、植物产品、机械刺激或三磷酸腺苷敏感的不同受体的表达进行分子区分。
于许多这些分子,包括电压门控 Na
+
通道的 Nav1.7 亚型,仅在感觉神经元中表达,因此它们的选择性药理学靶
向暗示了一种镇痛药物开发的新方法。
4. 伤害受体终止于脊髓的背角,在那里它们激发中间神经元和投射神经元。神经肽也从伤害受体的外周末
端释放,并导致神经源性炎症,包括外周血管的血管扩张和外渗。开发降钙素基因相关肽抗体以阻断血管舒
是治疗偏头痛的新方法。
5. 背角投射神经元的主要大脑目标是腹后外侧丘脑,它处理疼痛刺激的位置和强度特征。其他神经元靶向
背外侧脑桥的臂旁核。反过来,臂旁核神经元投射到大脑的边缘区域,该区域处理疼痛体验的情感/情绪特征。
6. 异常性疼痛,由无害刺激产生的疼痛,部分是由于伤害受体的外周敏化引起的。当存在组织损伤和炎症
时会发生外周致敏,并涉及对非甾体抗炎药敏感的前列腺素的产生,从而降低激活伤害受体的阈值。非甾体
炎药的一大优势是它们作用于外周,说明了努力开发药物疗法的重要性,例如神经生长因子抗体,它不能穿
血脑屏障,从而减少它们在中枢神经系统中产生不良副作用的可能性系统。
7. 痛觉过敏(对疼痛刺激的反应加剧疼痛)和异常性疼痛也由背角活动改变引起,这是一种中枢敏化过程,
有助于疼痛传递神经元的自发活动和伤害感受信号的放大。脊髓 N-甲基-D-天冬氨酸受体的谷氨酸激活以及小胶
质细胞和星形胶质细胞的激活尤其有助于周围神经损伤后可能发生的神经性疼痛。了解中枢敏化的后果对于
止从急性疼痛转变为慢性疼痛至关重要。
8. 在正常情况下,大直径非伤害性传入神经的输入可以通过在背角接合 γ-氨基丁酸能抑制回路来减少伤害
性信息向大脑的传输。这种抑制控制是振动和经皮电刺激产生的疼痛缓解的基础。然而,当损伤诱导中枢敏
时,Aβ 输入介导机械异常性疼痛。
9. 阿片类药物是治疗剧烈疼痛最有效的药理工具。阿片类药物和相关内源性阿片肽的抑制作用是由神经递
质释放减少或突触后神经元超极化引起的。阿片受体拮抗剂纳洛酮可以阻断所有阿片样物质的作用。
10. 内源性阿片类药物,包括脑啡肽和强啡肽,及其阿片类药物受体靶点不仅仅在大脑的疼痛相关区域表达。
因此,阿片类药物的全身给药与许多不良副作用有关,包括便秘、呼吸抑制和奖励系统激活。后者可能导致心理
依赖和最终滥用。许多这些不良副作用限制了阿片类药物用于长期疼痛控制的使用。
11. 大脑不仅接收导致疼痛感知的伤害感受信息,而且还通过内啡肽介导的疼痛控制系统调节脊髓的输出以
减轻疼痛。中脑导水管周围灰质的电刺激可以激活下行抑制控制系统,可能涉及内啡肽,从而减少疼痛信息
脊髓传递到大脑。
12. 一些心理操作(例如,安慰剂镇痛)产生的疼痛缓解涉及内啡肽释放;其他操作,例如催眠,则不会。
13. 长期使用阿片类药物会产生耐受性和心理依赖性。耐受性表现为需要更高剂量的阿片剂才能达到相同的
生理终点。相比之下,心理依赖涉及大脑奖励系统的激活和可能导致滥用的渴望的发展。
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